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Chronic nicotine and synaptic transmission in brainstem respiratory neurons

脑干呼吸神经元的慢性尼古丁和突触传递

基本信息

批准号：
10401834
负责人：
Ralph Frank Fregosi
金额：
$ 37.4万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401834
关键词：
ARHGEF5 gene Acetylcholine Action Potentials Acute Adolescence Age Animals Attenuated Birth Brain Brain Stem Breathing Carbon Dioxide Cells Chronic Data Deglutition Dendrites Development Devices Electronic cigarette Electrophysiology (science)Experimental Designs Exposure to Glutamates Glycine Goals Growth Homeostasis Human Milk Hypercapnia Immunohistochemistry In Vitro Injections Life Longevity Maintenance Mastication Measurement Membrane Membrane Potentials Mothers Motor Motor Neurons Muscle Nervous system structure Neuroanatomy Neurons Neurotransmitter Receptor Neurotransmitters Newborn Animals Nicotine Nicotinic Receptors Outcome Output Pattern Physicians Physiological Play Plethysmography Process Progress Reports Property Protocols documentation Pump Rattus Resistance Respiration Role Smokeless Structure Synapses Synaptic Transmission System Techniques Testing Time Tongue Weaning Work critical period drinking water electronic cigarette use experimental study gamma-Aminobutyric Acid gender difference hookah in utero in vivo neonatal period nervous system development nicotine exposure nicotine gum nicotine patch nicotine use patch clamp postnatal postsynaptic prenatal prenatal cigarette smoking prenatal exposure prenatal nicotine exposure presynaptic receptor expression relating to nervous system respiratory response sex social stressor suckling voltage

项目摘要

Despite a growing body of evidence showing that in utero nicotine exposure leads to aberrant development of brainstem neurons involved in the maintenance of key homeostatic functions such as breathing, the consumption of nicotine via smokeless nicotine delivery devices (e.g., e-cigarettes, water pipes, nicotine patches or gum) more than doubled between 2008-2012. A particular concern is raised by recent studies showing that 30% of pregnant smokers were advised to use nicotine patches or gum by their physician. To date, the majority of the data on nicotine exposure and development of brainstem neurons has focused on how in utero exposure alters the brains of very young neonatal animals. As a result, we do not know if the changes observed with in utero exposure resolve or persist with maturation, or worsen if exposure continues after birth. The specific objective of this application is to test the hypothesis that prenatal and/or postnatal exposure to nicotine alters the structure and function of brainstem neurons that control the muscles of the tongue (hypoglossal motor neurons, XIIMNs), using an in vitro approach, as well as the breathing-related control of the tongue muscles, using an in vivo approach. The tongue muscles participate in breathing, swallowing, suckling and mastication, and therefore are critical for organismal homeostasis. A key focus is whether abnormal development of the tongue muscle motor system is worsened if nicotine exposure continues after birth, or if the alterations persist or are attenuated if exposure ends at weaning. Animals (rats) will be studied at key developmental time points, including the early neonatal period (postnatal day 1 (P1) - P5); the putative critical period for development of brainstem neurons (P10 - P12); the end of adolescence when brain maturation is largely complete (P50 – P60); and after sexual and social maturity (4 – 6 months). Specific Aims: We will use neuroanatomy, immunohistochemistry, patch clamp electrophysiology and in vivo plethysmography and EMG recordings to examine how prenatal and/or postnatal nicotine exposure alters: 1) the dendrite branching pattern and the expression of inhibitory (GABA, glycine) and excitatory (glutamate) neurotransmitter receptors on XIIMNs; 2) development of important neuron membrane properties (resting potential, voltage threshold for spike initiation, etc.), the cell's response to excitatory and inhibitory neurotransmitters; 3) development of the breathing pattern and the function of tongue muscles during normal, quiet breathing and when breathing is increased in response to an acute nicotine challenge or by increasing inspired carbon dioxide. The proposed experiments will result in a comprehensive understanding of how in utero and life-long nicotine exposure alters development of brainstem motoneurons that are critical for survival.

尽管越来越多的证据表明，在子宫内接触尼古丁会导致异常的脑干神经元的发育参与维持关键的稳态功能，呼吸，通过无烟尼古丁输送装置消耗尼古丁（例如，电子烟，水管、尼古丁贴片或口香糖）的数量在2008年至2012年期间增加了一倍多。特别关注的问题最近的研究表明，30%的怀孕吸烟者被建议使用尼古丁，贴片或口香糖。到目前为止，大多数关于尼古丁暴露的数据，脑干神经元的发育集中在子宫内暴露如何改变大脑，年轻的新生动物。因此，我们不知道子宫内暴露所观察到的变化是否随着成熟而消退或持续，或者如果出生后继续暴露则恶化。具体目标本申请的目的是检验产前和/或产后暴露于尼古丁改变脑干神经元的结构和功能控制的肌肉的舌头（舌下神经运动神经元，XIMNs），以及呼吸相关的控制，舌头肌肉，使用体内方法。舌头肌肉参与呼吸，吞咽，哺乳和咀嚼，因此对生物体内平衡至关重要。一个关键的焦点是如果尼古丁暴露，舌肌运动系统的异常发育是否恶化出生后继续，或者如果改变持续存在或在断奶时暴露结束时减弱。将在关键发育时间点（包括新生早期）对动物（大鼠）进行研究（出生后第1天（P1）- P5）;脑干神经元发育的假定关键期（P10 -P5）。 P12）;青春期结束时，大脑成熟基本完成（P50 - P60）;以及性和社会成熟度（4 - 6个月）。具体目标：我们将使用神经解剖学，免疫组织化学、膜片钳电生理学和体内体积描记术和EMG 记录，以检查产前和/或产后尼古丁暴露如何改变：1）树突分支模式和抑制性（GABA，甘氨酸）和兴奋性（谷氨酸）的表达 XIIMNs上的神经递质受体; 2）重要神经元膜特性的发展（静息电位、尖峰起始的电压阈值等），细胞对兴奋性和抑制性神经递质; 3）呼吸模式和舌功能的发育肌肉在正常，安静的呼吸和呼吸增加时，以响应急性尼古丁挑战或增加吸入的二氧化碳。拟议的实验将导致一个全面了解子宫内和终生尼古丁暴露如何改变脑干运动神经元对生存至关重要。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmental nicotine exposure disrupts dendritic arborization patterns of hypoglossal motoneurons in the neonatal rat.

发育过程中的尼古丁暴露会破坏新生大鼠舌下运动神经元的树突状树枝化模式。

DOI：
10.1002/dneu.22379
发表时间：
2016
期刊：
Developmental neurobiology
影响因子：
3
作者：
Powell,GregoryL;Gaddy,Joshua;Xu,Fei;Fregosi,RalphF;Levine,RichardB
通讯作者：
Levine,RichardB

Current injection and receptor-mediated excitation produce similar maximal firing rates in hypoglossal motoneurons.

电流注射和受体介导的兴奋在舌下运动神经元中产生相似的最大放电率。

DOI：
10.1152/jn.00848.2015
发表时间：
2016
期刊：
Journal of neurophysiology
影响因子：
2.5
作者：
Wakefield,HilaryE;Fregosi,RalphF;Fuglevand,AndrewJ
通讯作者：
Fuglevand,AndrewJ

Developmental nicotine exposure alters AMPA neurotransmission in the hypoglossal motor nucleus and pre-Botzinger complex of neonatal rats.

DOI：
10.1523/jneurosci.3711-12.2013
发表时间：
2013-02-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Jaiswal SJ;Pilarski JQ;Harrison CM;Fregosi RF
通讯作者：
Fregosi RF

Influence of developmental nicotine exposure on glutamatergic neurotransmission in rhythmically active hypoglossal motoneurons.

发育期尼古丁暴露对节律性活跃舌下运动神经元谷氨酸能神经传递的影响。